Many new and also existing drugs, including vaccines, antigen-presenting cells, therapeutic antibodies, proteins, peptides and DNA constituents, have been developed for better and more efficient treatment for disease and illness. Especially due to recent advances in molecular biology and biotechnology, increasingly potent pharmaceutical agents, such as recombinant human insulin, growth hormone, follicle stimulating hormone, parathyroid hormone, etanercept, and erythropoietin are available. However, one significant limitation in using these new drugs is often a lack of an efficient drug delivery system, especially where the drug needs to be transported across one or more biological barriers at therapeutically effective rates and amounts.
Most drugs are orally administered. However, many drugs, especially protein based drugs (e.g., proteins, peptides, and/or nucleic acids, etc.) cannot be effectively absorbed in this manner due to their degradation in the gastrointestinal tract, poor absorption in intestinal membrane, and/or first pass breakdown by the liver. Thus the bioavailability is very poor, so that very high dose rates have to be applied. To circumvent such difficulties, parenteral administration can be employed. Typically such administration relies on injection of the drug into the patient's circulatory system or muscle tissue or intracutaneous or subcutaneous tissue using standard syringes or catheters. Especially in paediatrics intraosseous applications are used in case of emergency. Unfortunately, needle injection often provokes needle phobia, substantial pain, and/or local damage to the skin in many patients. Moreover, and especially where needle injection-based access to body fluids is required for long-term drug administration, numerous challenges arise. For example, needles tend to clog when left over a prolonged period in a patient's vascular system. Also, mobility of the patient is generally limited. Moreover, needles and catheters might cause infections. Moreover the safe disposal of needles is difficult and expensive, and infection rate by recapping of needles is high.
Alternatively, transmembrane delivery can be employed which usually relies on passive diffusion of a drug across a biological membrane such as the skin. However, transmembrane, in particular transdermal delivery is often not broadly applicable as the skin presents a relatively effective barrier for numerous drugs. The outermost layer of skin, the stratum corneum, is chiefly responsible for the well known barrier properties of skin. Thus, it is this layer that presents the greatest barrier to transdermal flux of drugs or other molecules with a molecular weight of greater than about 500 Dalton into the body. Also the lipophilic or hydrophilic properties, polarity and solubility are important factors for transdermal permeability. Once a drug reaches the dermal region, which is below the epidermal layer, the drug diffuses rapidly to deep tissue layers and other parts of the system via blood circulation. To improve the rate of drug delivery through the skin, chemical enhancers, iontophoresis, electroporation, ultrasound, and heat elements have been used. However, and depending on the particular drug, such techniques frequently fail to provide a therapeutic level of delivery. Worse yet, such techniques will sometimes provoke undesirable skin reactions for long term drug delivery.
Some attempts have been made to improve transdermal delivery using a laser for puncturing the skin of a patient in a manner that does not result in bleeding. Such perforation typically penetrates through the stratum corneum or both the stratum corneum and the epidermis. This allows drug delivery through the skin. An example of such a laser, described in EP 1133953, provides one slit-shaped perforation with a width of up to 0.5 mm and a length of up to 2.5 mm. (This and all other citations herein are incorporated by reference in their entirety). Unfortunately, the rate of drug delivery through such a perforation is limited. This perforation also provokes undesirable skin reactions and the perforation of the skin frequently causes pain. The perforation requires subsequent patch drug application. However, such administration of drugs often results in inconsistent drug dosages, inconvenient usage, and sometimes even in infections.
Document U.S. Pat. No. 6,328,733 discloses a laser porator using a Gaussian laser beam and creating a series of holes or slits onto the scalp for hair transplant. The size and depth of the created holes or slits is relatively large, and they are not suitable for transdermal drug delivery.
Document WO00/78242 discloses a laser porator for forming micropores in the stratum corneum using a Gaussian laser beam. The purpose of this laser porator is to easily gather interstitial fluids for testing analytes present in the fluid. The micropores created with this laser porator are also not suitable for transdermal drug delivery. A further drawback of this laser porator is that if provided with a portable power supply, such as a battery, the total operation time of the laser porator is very short.
Therefore, although there are various methods and devices for drug administration known in the art, all or almost all of them suffer from one or more disadvantages. Among other things, currently known methods and devices fail to allow controlled and reproducible administration of drugs. Currently known methods and devices also fail to provide prompt initiation and cut-off of drug delivery with improved safety, efficiency and convenience. Currently known devices are also limited in forming micropores. Currently known devices are also either not portable or can not be operated during a reasonable time if provided with a portable power supply. It is therefore an object of the present invention to provide devices and methods to improve transmembrane delivery of molecules, including drugs and biological molecules, across biological membranes, such as tissue or cell membranes. This problem is solved with a laser microporator according to the inventive subject matter presented herein.